U.S. patent application number 12/441674 was filed with the patent office on 2010-01-28 for reaction apparatus, and reaction method.
Invention is credited to Yasuo Nakanishi, Yuichi Oda, Noriyuki Yoneda.
Application Number | 20100022771 12/441674 |
Document ID | / |
Family ID | 39200459 |
Filed Date | 2010-01-28 |
United States Patent
Application |
20100022771 |
Kind Code |
A1 |
Yoneda; Noriyuki ; et
al. |
January 28, 2010 |
REACTION APPARATUS, AND REACTION METHOD
Abstract
The present invention is directed at obtaining a high yield of a
target substance and simultaneously securing high productivity. A
reaction apparatus 10 has: a main flow channel 12 having an inner
diameter of 3 mm, in which a raw material M.sub.1 flows; an
introduction flow channel 14 in which a raw material M.sub.2 that
causes a chemical reaction with the raw material M.sub.1 flows; and
five branch introduction flow channels 16a to 16e which are
branched from the introduction flow channel 14 and introduce the
raw material M.sub.2 to the main flow channel 12, at predetermined
introduction points 12o to 12s in the main flow channel 12. Here,
in the main flow channel 12, the flow channel lengths of the flow
channels 12b to 12d between adjacent introduction points 12p to 12s
are not longer than those of the flow channels 12a to 12c between
the next previous adjacent introduction points 12o to 12r in a flow
direction of the raw material M.sub.1. At least one length of the
flow channels 12b to 12d between the adjacent introduction points
12p to 12s is shorter than lengths of the flow channels 12a to 12c
between previous adjacent introduction points 12o to 12r in the
flow direction of the raw material M.sub.1.
Inventors: |
Yoneda; Noriyuki;
(Kumagaya-Shi, JP) ; Oda; Yuichi; (Saitama,
JP) ; Nakanishi; Yasuo; (Saitama, JP) |
Correspondence
Address: |
MERCK AND CO., INC
P O BOX 2000
RAHWAY
NJ
07065-0907
US
|
Family ID: |
39200459 |
Appl. No.: |
12/441674 |
Filed: |
September 14, 2007 |
PCT Filed: |
September 14, 2007 |
PCT NO: |
PCT/JP2007/067949 |
371 Date: |
April 1, 2009 |
Current U.S.
Class: |
544/350 ;
422/211; 562/596 |
Current CPC
Class: |
C07C 67/343 20130101;
B01J 2219/00063 20130101; B01J 19/243 20130101; C07C 67/343
20130101; C07D 487/04 20130101; C07C 69/716 20130101 |
Class at
Publication: |
544/350 ;
422/211; 562/596 |
International
Class: |
C07D 487/02 20060101
C07D487/02; B01J 19/00 20060101 B01J019/00; C07C 55/06 20060101
C07C055/06 |
Foreign Application Data
Date |
Code |
Application Number |
Sep 19, 2006 |
JP |
2006-253218 |
Claims
1. A reaction apparatus having a main flow channel which has a
cross-section area corresponding to an area of a circle having a
diameter of 0.5 to 6 mm and in which a first fluid flows, an
introduction flow channel in which a second fluid that causes a
chemical reaction with the first fluid flows, and three or more
branch introduction flow channels which are branched from the
introduction flow channel and introduce the second fluid to the
main flow channel at predetermined introduction points in the main
flow channel, wherein, a flow channel length between adjacent
introduction points in the main flow channel is not longer than a
flow channel length between next previous adjacent introduction
points in a flow direction of the first fluid, and at least one
flow channel length between the adjacent introduction points is
shorter than flow channel lengths between previous adjacent
introduction points in the flow direction of the first fluid.
2. The reaction apparatus according to claim 1, wherein the
reaction apparatus further has temperature control means for
controlling the temperature of the main flow channel and the
vicinity of the introduction point in the branch introduction flow
channel.
3. The reaction apparatus according to claim 1 or, wherein the
cross-section area of the main flow channel is equivalent to the
area of a circle having a diameter of 1 to 3 mm.
4. The reaction apparatus according to claim 1, wherein the
introduction point is structured by a 180-degree T-shaped mixture
channel, and the branch introduction flow channel is
perpendicularly connected to the main flow channel.
5. The reaction apparatus according to claim 1, wherein the number
of the branch introduction flow channels is 5 to 10.
6. The reaction apparatus according to claim 1, wherein the
reaction apparatus further has a first adjusting flow channel for
adjusting the temperature of the first fluid before the first fluid
is supplied to the main flow channel, and a second adjusting flow
channel for adjusting the temperature of the second fluid before
the second fluid is supplied to the introduction flow channel.
7. The reaction apparatus according to claim 1, wherein the main
flow channel, the introduction flow channel and the branch
introduction flow channel have the same cross-section area, and the
branch introduction flow channels have the same flow channel
length.
8. The reaction apparatus according to claim 1, wherein the main
flow channel and the branch introduction flow channel have the
cross-section areas not larger than that of the introduction flow
channel, and the branch introduction flow channels have the same
flow channel length.
9. The reaction apparatus according to claim 1, wherein the main
flow channel and the branch introduction flow channel have the
cross-section areas not larger than that of the introduction flow
channel, and the branch introduction flow channel has a flow
channel length not shorter than that of a branch introduction flow
channel to be connected to the main flow channel at the
introduction point next previous to the introduction point of the
branch introduction flow channel, in the flow direction of the main
flow channel.
10. The reaction apparatus according to claim 1, wherein the
reaction apparatus further has a first pump which supplies the
first fluid to the main flow channel, and a second pump which
supplies the second fluid to the introduction flow channel.
11. The reaction apparatus according to claim 10, wherein the first
pump and the second pump are a double diaphragm pump which employs
a non-circular cam therein.
12. A reaction method using the reaction apparatus according to
claim 1, wherein the reaction method passes a fluid containing a
nucleophilic organometallic compound as one of the first fluid and
the second fluid, and passes a fluid containing a compound which
causes an addition reaction or an exchange reaction with the
nucleophilic organometallic compound, as the other fluid.
13. The reaction method according to claim 12, wherein the reaction
method passes the fluid containing the nucleophilic organometallic
compound, as the second fluid, and passes the fluid containing the
compound which causes the addition reaction or the exchange
reaction with the nucleophilic organometallic compound, as the
first fluid.
14. The reaction method according to claim 12, wherein the first
fluid and the second fluid contain at least one type of solvent
selected from the group consisting of tetrahydrofuran, diethyl
ether, dioxane and dibutyl ether.
15. The reaction method according to claim 12, wherein the fluid
containing the nucleophilic organometallic compound out of the
first fluid and the second fluid contains at least one type of
solvent selected from the group consisting of tetrahydrofuran,
diethyl ether, dioxane and dibutyl ether, and the fluid containing
the compound which causes the addition reaction or the exchange
reaction with the nucleophilic organometallic compound does not
contain a solvent.
16. The reaction method according to claim 12, wherein the
nucleophilic organometallic compound is at least one type of
nucleophilic organometallic compound selected from the group
consisting of an organomagnesium compound, an organolithium
compound, an organozinc compound, an organocadmium compound and an
organosodium compound.
17. The reaction method according to claim 16, wherein the
organomagnesium compound is a Grignard reagent.
18. The reaction method according to claim 12, wherein the compound
which causes the addition reaction or the exchange reaction with
the nucleophilic organometallic compound is a carbonyl
compound.
19. The reaction method according to claim 12, wherein the
nucleophilic organometallic compound is
1-bromomagnesium-5-chloropentane, and the compound which causes the
addition reaction or the exchange reaction with the nucleophilic
organometallic compound is diethyl oxalate.
20. A reaction method using the reaction apparatus according to
claim 1, wherein the reaction method passes a fluid containing a
catalyzer for a reaction selected from hydrogenation or reduction
and hydrogen, as one of the first fluid and the second fluid, and
passes a fluid containing a substrate for the reaction, as the
other.
21. The reaction method according to claim 20, wherein the reaction
method passes the fluid containing the catalyzer which is made for
a hydrogenation reaction from a metallic complex having ferroceno
phosphine as a ligand, and hydrogen, as one of the first fluid and
the second fluid, and passes a fluid containing an unsaturated
compound, as the other.
22. The reaction method according to claim 21, wherein the metal
complex is a rhodium complex having ferroceno phosphine as a
ligand.
Description
CROSS REFERENCE TO RELATED APPLICATION
[0001] This is the U.S. National Phase application under 35 U.S.C.
.sctn.371 of International Patent Application No.
PCT/JP2007/067949, filed Sep. 14, 2007 and claims the benefit of
Japanese Application No. 2006-253218, filed Sep. 19, 2006. The
International Application was published in Japanese of Mar. 27,
2008 as International Patent Publication No. WO 2008/035633 under
PCT Article 21(2), and all preceding applications are incorporated
herein in their entirety.
TECHNICAL FIELD
[0002] The present invention relates to a reaction apparatus which
brings two types of fluids into a chemical reaction with each other
and a reaction method therefor.
BACKGROUND OF THE INVENTION
[0003] A conventional reaction apparatus has been proposed which
brings two types of fluids into a chemical reaction with each other
in a flow channel having a fine cross-section area so as to bring
the two types of fluids into an efficient chemical reaction (see
Japanese Patent Laid-Open No. 2002-292271, for instance). This
reaction apparatus can increase its specific surface (surface area
per unit volume) of a reacting substance in a flow channel to be a
reacting channel, in comparison with a conventional reaction method
in a batch process, and accordingly can obtain high heat-removal
efficiency. Thereby, the reaction apparatus can precisely control a
reaction temperature, can realize a reaction under an ideal
condition, and can realize an efficient reaction and a high yield.
Particularly, when being applied to a reactant which causes a large
exothermic reaction, the reaction apparatus can enhance a high
yield. In recent years, an example according to the technology is
described in which the apparatus uses a pipe having the inner
diameter of 2 mm for a static mixer and has almost such a practical
scale as to correspond to a volume of a production of 500 ml/min
(see the following Patent document 2, for instance).
[0004] [Patent document 1]: Japanese Patent Laid-Open No.
2002-292271
[0005] [Patent document 2]: National Publication of International
Patent Application No. 2003-523960
DISCLOSURE OF THE INVENTION
Problem to be Solved by the Invention
[0006] A reaction apparatus having a diameter of a flow channel of
approximately several hundreds .mu.m (hereinafter referred to as
microreactor) has been actively studied so far. However, when
considering an industrial application, the reaction apparatus
having the flow channel with a diameter of the above described size
causes a problem of a plug-up in the flow channel due to a small
dirt which has entered in a fluid and a crystal which has been
formed through a fluid reaction. Particularly, some nucleophilic
organometallic compound such as a Grignard reagent precipitates in
the vicinity of 0.degree. C. Then, the Grignard reagent approaches
a temperature of a refrigerant in the flow channel because the
microreactor effectively cools the Grignard reagent, and a speed in
the flow channel is low, so that the plug-up of the flow channel
tends to occur due to the precipitate. In addition, a temperature
of the precipitation temperature or lower cannot be employed
because of such a problem, which has been disadvantageous in a
yield of a target substance.
[0007] In addition, it is difficult for the microreactor to make a
fluid of a reacting substance flow at a larger flow rate than 20
ml/min. The microreactor also uses a pipe with a small diameter.
From these reasons, it is difficult for the microreactor to secure
sufficiently high productivity.
[0008] On the other hand, it is considered to simply increase the
diameter to several millimeters. The method solves the problem of
plug-up of the flow channel, but hardly provides the same heat
removal efficiency as in the microreactor, and accordingly
decreases the yield.
[0009] The present invention is designed at solving the above
described problems, and is directed at providing a reaction
apparatus which can provide a high yield of a target substance and
secure high productivity, and providing a reaction method
therefor.
SUMMARY OF THE INVENTION
[0010] A reaction apparatus according to the present invention
having a main flow channel which has a cross-section area
corresponding to an area of a circle having a diameter of 0.5 to 6
mm and in which a first fluid flows, an introduction flow channel
in which a second fluid that causes a chemical reaction with the
first fluid flows, and three or more branch introduction flow
channels which are branched from the introduction flow channel and
introduce the second fluid to the main flow channel at
predetermined introduction points in the main flow channel is
characterized in that a flow channel length between adjacent
introduction points in the main flow channel is not longer than a
flow channel length between next previous adjacent introduction
points in a flow direction of the first fluid, and at least one
flow channel length between the adjacent introduction points is
shorter than flow channel lengths between previous adjacent
introduction points in the flow direction of the first fluid.
[0011] In the reaction apparatus according to the present
invention, the second fluid is introduced into the main flow
channel at three or more introduction points of the main flow
channel, and accordingly the reaction between the first fluid and
the second fluid can proceed step by step. Thereby, the reaction
apparatus can inhibit the temperature at one introduction point
from rising due to the introduction of the second fluid. In the
reaction apparatus according to the present invention, a
temperature rise at an introduction point is lower as the
introduction point is located downstream in a flow direction of the
main flow channel, but the reaction apparatus has a structure in
which a flow channel length between the adjacent introduction
points in the flow direction of the first fluid is set so as not to
be longer than a flow channel length between the next previous
adjacent introduction points in the flow direction of the first
fluid, and at least one flow channel length between the adjacent
introduction points is shorter than a flow channel length between
the previous adjacent introduction points in the flow direction of
the first fluid, and accordingly can adequately remove the heat.
From these reasons, the reaction apparatus according to the present
invention can provide high heat-removal efficiency, and accordingly
can provide a high yield of a target substance.
[0012] In a reaction system using a large tank, the temperature
change needs to be reduced by diluting a compound with a solvent
and increasing the heat capacity, in order to practically control
the temperature rise due to a reaction heat. On the other hand, the
reaction apparatus according to the present invention can control
the temperature to a target temperature without diluting the
compound with the solvent. The reaction apparatus according to the
present invention has a larger cross-section area of the flow
channel than a microreactor, and thereby can prevent the plug-up of
the flow channel and can secure high productivity.
[0013] The reaction apparatus desirably further has temperature
control means for controlling the temperature of the main flow
channel and the vicinity of the introduction point in the branch
introduction flow channel. The reaction apparatus having such a
structure can surely implement the present invention.
[0014] The cross-section area of the main flow channel is desirably
equivalent to the area of a circle having a diameter of 1 to 3 mm.
The reaction apparatus having such a structure can provide a more
preferable result in at least any one of the yield and the
productivity.
[0015] The introduction point is preferably structured by a
180-degree T-shaped mixture channel, and the branch introduction
flow channel is perpendicularly connected to the main flow channel.
The reaction apparatus having such a structure can easily implement
the present invention, and can realize the space saving of the
apparatus.
[0016] The number of the branch introduction flow channels is
desirably 5 to 10. The reaction apparatus having such a structure
can further distribute the temperature rise caused by a reaction
between the first fluid and the second fluid, and can surely show
an effect according to the present invention.
[0017] The reaction apparatus desirably has further a first
adjusting flow channel for adjusting the temperature of the first
fluid before the first fluid is supplied to the main flow channel,
and a second adjusting flow channel for adjusting the temperature
of the second fluid before the second fluid is supplied to the
introduction flow channel. The reaction apparatus having such a
structure can surely control the temperatures of the first fluid
and the second fluid.
[0018] The main flow channel, the introduction flow channel and the
branch introduction flow channel desirably have the same
cross-section area, and the branch introduction flow channels
desirably have the same flow channel length.
[0019] The main flow channel and the branch introduction flow
channel have desirably the cross-section areas not larger than that
of the introduction flow channel, and the branch introduction flow
channels have desirably the same flow channel length
[0020] The main flow channel and the branch introduction flow
channel have desirably cross-section areas not larger than that of
the introduction flow channel, and the branch introduction flow
channel has a flow channel length not shorter than that of a branch
introduction flow channel to be connected to the main flow channel
at the introduction point next previous to the introduction point
of the branch introduction flow channel, in the flow direction of
the main flow channel.
[0021] The reaction apparatus desirably has further a first pump
which supplies the first fluid to the main flow channel, and a
second pump which supplies the second fluid to the introduction
flow channel. The reaction apparatus having such a structure can
surely use the reaction apparatus according to the present
invention.
[0022] The first pump and the second pump are desirably a double
diaphragm pump which employs a non-circular cam therein. The
reaction apparatus having such a structure can make a pulsating
flow in the fluid small, can stably obtain a high yield due to an
accurate flow rate, and can surely show the effect according to the
present invention. Furthermore, the reaction apparatus can
continuously supply a fluid having high reliability for a long
period of time without making a fine solid such as dirt in the
fluid caught in the pump.
[0023] By using the above described reaction apparatus, various
reactions are enabled.
[0024] Specifically, a reaction method using the above described
reaction apparatus can be implemented that passes a fluid
containing a nucleophilic organometallic compound as one of the
first fluid and the second fluid, and passes a fluid containing a
compound which causes an addition reaction or an exchange reaction
with the nucleophilic organometallic compound, as the other
fluid.
[0025] Though the structure varies according to the characteristics
of the reaction and a target compound to be obtained, a by-product
of a sequential reactant tends to be formed by a further progressed
synthesis reaction than a target compound, when the nucleophilic
organometallic compound excessively exists with respect to a
compound which causes the addition reaction or the exchange
reaction with the nucleophilic organometallic compound. For this
reason, it is preferable to pass the fluid containing the
nucleophilic organometallic compound as the second fluid, and to
pass the fluid containing the compound which causes the addition
reaction or the exchange reaction with the nucleophilic
organometallic compound as the first fluid. The reaction apparatus
having such a structure can complete the reaction in the vicinity
of the introduction point, does not increase the concentration of
the nucleophilic organometallic compound in the reaction fluid,
produces few by-products and can produce with high efficiency.
[0026] In addition, the reaction apparatus can sequentially and
efficiently react a fluid which causes a chemical reaction with the
obtained product. Specifically, the sequential reaction can be
efficiently carried out through two continuous reaction
apparatuses, by passing a fluid obtained as a product from the
reaction apparatus through a reaction apparatus having the same
structure, as any one of the first fluid and the second fluid, and
passing a fluid which causes a chemical reaction with the obtained
product as the other fluid.
[0027] In order to enhance the reactivity, the first fluid and the
second fluid preferably contain at least one type of solvent
selected from the group consisting of tetrahydrofuran, diethyl
ether, dioxane and dibutyl ether.
[0028] In this case, it is possible to make a fluid containing the
nucleophilic organometallic compound out of the first fluid and the
second fluid contain at least one type of solvent selected from the
group consisting of tetrahydrofuran, diethyl ether, dioxane and
dibutyl ether, and make the fluid containing the compound which
causes the addition reaction or the exchange reaction with the
nucleophilic organometallic compound contain no solvent. The
reaction apparatus having such a structure can provide a target
substance having high concentration.
[0029] The nucleophilic organometallic compound shall preferably be
at least one compound selected from the group consisting of an
organomagnesium compound (Grignard reagent, in particular), an
organolithium compound, an organozinc compound, an organocadmium
compound and an organosodium compound. In addition, the compound
which causes the addition reaction or the exchange reaction with
the nucleophilic organometallic compound is preferably a carbonyl
compound.
[0030] Such a nucleophilic organometallic compound has excellent
reactivity with a reactive substrate such as a carbonyl compound,
and can produce a target substance at a high yield. A specific
example of a reaction with the use of the carbonyl compound
includes a reaction between 1-bromomagnesium-5-chloropentane
employed as the nucleophilic organometallic compound and diethyl
oxalate employed as a compound which causes the addition reaction
or the exchange reaction with the nucleophilic organometallic
compound.
[0031] A reaction apparatus according to the present invention can
also be applied to other reactions than the above described
reactions. For instance, the reaction apparatus can be applied to a
reaction method of passing a fluid containing a catalyzer for a
reaction selected from hydrogenation or reduction and hydrogen as
one of the first fluid and the second fluid, and passing a fluid
containing a substrate for the reaction as the other.
[0032] In this case, it is preferable to pass a fluid containing
the catalyzer which is made for a hydrogenation reaction from a
metallic complex having ferroceno phosphine as a ligand, and
hydrogen, as one of the first fluid and the second fluid, and to
pass a fluid containing an unsaturated compound as the other. In
this case, a rhodium complex having ferroceno phosphine as a ligand
is particularly suitable for the metallic complex.
[0033] According to the present invention, high heat removal
efficiency can be obtained, and accordingly a high yield of a
target substance can be obtained. A reaction apparatus according to
the present invention has a larger cross-section area of a flow
channel than a microreactor, and accordingly can prevent the
plug-up of the flow channel and can secure the high
productivity.
BRIEF DESCRIPTION OF THE DRAWINGS
[0034] FIG. 1 is a block diagram of a reaction apparatus according
to an embodiment of the present invention;
[0035] FIG. 2 is another block diagram of a reaction apparatus
according to an embodiment of the present invention;
[0036] FIG. 3 is a view of a reaction apparatus according to an
embodiment of the present invention, which is viewed from an upper
part; and
[0037] FIG. 4 is a view of a reaction apparatus according to an
embodiment of the present invention, which is viewed from a side
face.
DETAILED DESCRIPTION OF THE INVENTION
[0038] Embodiments of a reaction apparatus according to the present
invention will now be described below with reference to the
drawings. In the description for the drawings, the same elements
are identified by the same reference numerals, and overlapping
descriptions are omitted.
[0039] FIG. 1 illustrates a reaction apparatus 10 according to the
present embodiment. The reaction apparatus 10 is an apparatus for
producing a target substance by bringing raw materials M.sub.1 and
M.sub.2 which are two types of fluids into a chemical reaction in a
flow channel. The reaction apparatus 10 has a main flow channel 12
in which the raw material M.sub.1 of a first fluid flows, and an
introduction flow channel 14 in which the raw material M.sub.2 of a
second fluid flows. The main flow channel 12 and the introduction
flow channel 14 are composed of, for instance, a circular pipe
which is made from stainless and has the inner diameter of 3 mm and
the outer diameter of 4 mm.
[0040] Each of the flow channels 12 and 14 needs not to employ the
circular pipe, but the flow channel 12 employs a pipe having the
cross-section area equivalent to the area of a circle having a
diameter (inner diameter) of 0.5 to 6 mm from the viewpoint of the
productivity of the target substance and the like. That is to say,
the equivalent diameter of the main flow channels 12 is set at 0.5
to 6 mm. In addition, the equivalent diameter is desirably set at 1
to 3 mm from at least any one viewpoint of the yield and the
productivity.
[0041] The main flow channel 12 and the introduction flow channel
14 are connected to each other through a plurality of branch
introduction flow channels 16a to 16e. The branch introduction flow
channels 16a to 16e are branched at branch points 14o to 14s from
the introduction flow channel 14 respectively, are connected to the
main flow channel 12 at predetermined introduction points 12o to
12s in the main flow channel 12, and introduce the material M.sub.2
flowing in the introduction flow channel 14 into the main flow
channel 12. The branch introduction flow channels 16a to 16e are
perpendicularly connected to the introduction flow channel 14 at
the branch points 14o to 14s. Specifically, the branch points 14o
to 14s is composed of, for instance, a 180-degree T-shaped mixture
flow channel made from stainless steel, and can employ, for
instance, a T-shaped joint made by Swagelok Company.
[0042] The material M.sub.2 which has been introduced into the main
flow channel 12 through the branch introduction flow channels 16a
to 16e reacts with the material M.sub.1 which flows in the main
flow channel 12 to produce a target substance (or substance for
producing the target substance). The branch introduction flow
channels 16a to 16e are composed of, for instance, a circular pipe
which is made from stainless steel and has the inner diameter of 1
mm and the outer diameter of 3 mm.
[0043] In addition, the branch introduction flow channels 16a to
16e are perpendicularly connected to the main flow channel 12 at
the introduction points 12o to 12s. Specifically, the introduction
points 12o to 12s are composed of, for instance, a 180-degree
T-shaped mixture flow channel made from stainless steel (can employ
a T-shaped joint made by Swagelok Company, for instance). Note that
the pipe diameter and the length of the main flow channel 12, the
introduction flow channel 14 and each of the branch introduction
flow channels 16a to 16e are adjusted so that the flow rate of the
material M.sub.2 to be introduced into the main flow channel 12
from each of the branch introduction flow channels 16a to 16e can
be approximately equal, or the flow rate can be slightly more than
that of the branch introduction flow channels 16a to 16e to be
connected to the main flow channel 12 downstream in a flow
direction.
[0044] For instance, the main flow channel 12, the introduction
flow channel 14 and the branch introduction flow channels 16a to
16e may have the same equivalent diameter (that is to say, the same
cross-section area), and the branch introduction flow channels 16a
to 16e may have the same flow channel length with each other.
Furthermore, the main flow channel 12 and the branch introduction
flow channels 16a to 16e may have an equivalent diameter not larger
than the introduction flow channel 14 (specifically, the main flow
channel 12 and the branch introduction flow channels 16a to 16e
have cross-section areas not larger than the introduction flow
channel 14), and the branch introduction flow channels 16a to 16e
may have the same flow channel length with each other. More
preferably, the main flow channel 12 and the branch introduction
flow channels 16a to 16e have an equivalent diameter not larger
than the introduction flow channel 14, and the branch introduction
flow channels 16a to 16e may have the flow channel length not
shorter than that of the respective branch introduction flow
channels 16a to 16d which are connected to the main flow channel 12
at the respective next previous introduction points 12o to 12r of
the branch introduction flow channels 16b to 16e in a flow
direction of the main flow channel 12.
[0045] The branch introduction flow channels 16a to 16e may have
equivalent diameters not larger than that of the introduction flow
channel 14, and may be set at, for instance, 1 mm. When the flow
rate of the branch introduction flow channels 16a to 16e is set at
100 ml/min or more, the branch introduction flow channels 16a to
16e may have the equivalent diameter of 3 mm.
[0046] In the main flow channel 12, the flow channels 12a to 12d
from the respective introduction points 12o to 12r to next
respective introduction points 12p to 12s and the flow channel 12e
from the last introduction point 12s to an edge of a thermostatic
liquid tank 28 may be formed into a coil shape for space saving.
The branch introduction flow channels 16a to 16e may be similarly
formed into a coil shape.
[0047] In order to realize a simple structure, flow channels 14a to
14d between the branch points 14o to 14s of the introduction flow
channel 14 can have the same flow channel length. In this case, as
the branch introduction flow channels 16a to 16e are branched
downstream, the flow rate of a raw material M.sub.2 which is passed
as a branched flow increases. The flow channel lengths of the flow
channels 14a to 14d between the branch points 14o to 14s of the
introduction flow channel 14 shall be respectively equal to that of
the flow channels 12a to 12d between the introduction points 12o to
12s of the main flow channel 12 corresponding to the branch points
14o to 14s. Specifically, the flow channel 14a of the introduction
flow channel 14 has the same length as that of the flow channel 12a
of the main flow channel 12, and the flow channels 14b to 14d of
the introduction flow channel 14 also have their lengths similarly.
The reaction apparatus having such a structure can pass an almost
same amount of the raw material M.sub.2 in the branch introduction
flow channels 16a to 16e, and can provide a high yield, which is
preferable. Preferably, the flow channel lengths of the branch
introduction flow channels 16a to 16e are normally set at 0.5 m to
3.0 m, and can have the same length. Specifically, all lengths of
each of the branch introduction flow channels 16a to 16e are set at
0.5 m, for instance. Furthermore, the lengths are preferably set at
0.5 m, 1.5 m, 2.0 m, 2.5 m and 3.0 m respectively.
[0048] In the main flow channel 12, the flow channel lengths
between adjacent introduction points 12p to 12s in a flow direction
of the raw material M.sub.1 are not longer than the next previous
flow channel length between adjacent introduction points 12o to 12r
in the flow direction of the first fluid. In addition, at least one
of the flow channel lengths between adjacent introduction points
12p to 12s is shorter than the flow channel length between the next
previous adjacent introduction points 12o to 12r. Specifically, the
flow channel length of the flow channel 12a between the
introduction points 12o and 12p is set at 1 m, and the flow channel
length of the flow channels 12b to 12d between the adjacent
introduction points 12p to 12s other than the above flow channel
length is set at 0.5 m, for instance. This is because the
temperature rise in the introduction points 12o to 12s is lower in
a more downstream flow direction of the raw material M.sub.1 in the
main flow channel 12 and accordingly the structure can
appropriately remove the heat.
[0049] In the present embodiment, five branch introduction flow
channels 16a to 16e are installed, but at least three branch
introduction flow channels may be installed. The number of the
branch introduction flow channels is desirably 5 to 10. This is
because the temperature rise due to a chemical reaction between a
raw material M.sub.1 and a raw material M.sub.2 is further
distributed, and accordingly the structure can surely show an
effect of the present invention.
[0050] A first adjusting flow channel 18 which adjusts a raw
material M.sub.1 to an optimum temperature beforehand is provided
in an upstream direction of a first introduction point 12o of a
main flow channel 12. Specifically, the adjusting flow channel 18
is integrally composed with a circular pipe which constitutes the
main flow channel 12. A first pump 20 which supplies the raw
material M.sub.1 to the main flow channel 12 is provided in a
further upstream direction of the circular pipe. A container 22 for
collecting a produced liquid P which has been produced by a
reaction between the raw material M.sub.1 and the raw material
M.sub.2 is provided on the opposite end of the main flow channel
12.
[0051] A second adjusting flow channel 24 for adjusting the raw
material M.sub.2 to the optimum temperature beforehand is provided
in an upstream direction (in a flow direction of raw material
M.sub.2) of a point at which the branch introduction flow channel
16a firstly branches off from an introduction flow channel 14.
Specifically, the adjusting flow channel 24 is integrally composed
with a circular pipe which constitutes the introduction flow
channel 14. A second pump 26 which supplies the raw material
M.sub.2 to the introduction flow channel 14 is provided in a
further upstream direction of the circular pipe. It is preferable
to form the adjusting flow channels 18 and 24 into a coil shape for
space saving, similarly to the main flow channel 12 and the branch
introduction flow channels 16a to 16e.
[0052] The above described pumps 20 and 26 desirably employ a
double diaphragm pump which employs a non-circular cam so as to
make a pulsating current of a fluid to be supplied small. This pump
can employ specifically a smooth flow pump TPL1M or TLP2M made by
TACMINA CORPORATION, for instance.
[0053] The above described main flow channel 12, the introduction
flow channel 14, the branch introduction flow channels 16a to 16e,
and the adjusting flow channels 18 and 24 are arranged in a
thermostatic liquid tank 28. A refrigerant 30 is contained in the
thermostatic liquid tank 28, and cools fluids which flow through
the main flow channel 12, the introduction flow channel 14, the
branch introduction flow channels 16a to 16e and the adjusting flow
channels 18 and 24 (which are generically referred to as flowing
type fine reaction flow channel 32). The refrigerant 30 is kept at
a constant temperature by a temperature controller 34, a heat
exchanger 36 and a cooling pipe 38 which are provided on the
thermostatic liquid tank 28. In other words, the thermostatic
liquid tank 28, the refrigerant 30, the temperature controller 34,
the heat exchanger 36 and the cooling pipe 38 are temperature
control means for controlling the temperatures of the main flow
channel 12 and the branch introduction flow channels 16a to 16e.
However, the temperature control means does not necessarily need to
have the above described structure, but may be any means as long as
it appropriately controls the temperature. For instance, there is a
method of keeping the liquid in the tank at a constant temperature
by installing a cooler in the outside and directly circulating the
refrigerant 30 in the cooler without using the cooling pipe.
[0054] The temperature control means is directed at controlling the
temperature of a fluid which flows in the flow channel in the
vicinity of the introduction points 12p to 12s, in the main flow
channel 12 and the branch introduction flow channels 16a to 16e.
One thermostatic liquid tank 28 may be provided for the
flowing-type fine reaction flow channel 32 in order to simplify the
apparatus, and a refrigerant to be supplied may be controlled to
one temperature. Accordingly, the reaction heat to be removed is
adjusted with the flow channel length or the time in which the
fluid stays in the flow channel. That is to say, the temperature of
the fluid in the main flow channel 12 can be brought close to a
target temperature, by making at least one flow channel length
between adjacent introduction points 12p to 12s in a flow direction
of the M.sub.1 shorter than that between the next previous
introduction points in the main flow channel 12, in principle, as
was described above. The flow channel lengths of each of the flow
channels 12a to 12e are normally set at 0.5 m to 3.0 m, and as the
flow rate increases, the flow channel length increases.
[0055] On the other hand, the temperature of the fluid to be
supplied to the introduction points 12p to 12s from the branch
introduction flow channels 16a to 16e may be controlled by the flow
channel lengths of the branch introduction flow channels 16a to 16e
to be arranged in the thermostatic liquid tank 28. As the
temperature of the refrigerant is lower, the lengths of the flow
channels to be arranged are shorter, and as the flow rates of the
fluid to be passed to the branch introduction flow channels 16a to
16e are smaller, the lengths may be shorter. When a refrigerant at
-15 to -30.degree. C. is used, the apparatus may normally have a
structure as illustrated in FIG. 2 that will be described later, in
which the branch introduction flow channels 16a to 16e are arranged
in the thermostatic liquid tank 28 by the depth of approximately 5
cm. This is because when the nucleophilic organometallic compound
is passed in the branch introduction flow channels 16a to 16e, the
nucleophilic organometallic compound stably continues to flow in
the branch introduction flow channels for a long period of time
without causing plug-up. In this case, the heat is mainly removed
in the main flow channel 12. When the refrigerant at a temperature
of -5 to -15.degree. C. or higher is used, it is efficient to
arrange all branch introduction flow channels 16a to 16e in the
thermostatic liquid tank 28, as is illustrated in FIG. 1.
[0056] The temperature of the refrigerant 30 needs to be set at a
low temperature, as the flow rate (=flow rate of introduction flow
channel 14+flow rate of main flow channel 12) is larger, and as the
equivalent diameter of the main flow channel 12 is larger, so as to
provide desirable cooling efficiency. Normally, when the equivalent
diameter of the main flow channel 12 is 3 mm, the temperature is
set at -15 to -30.degree. C., and when the equivalent diameter is 1
mm, the temperature is set at -5 to -15.degree. C.
[0057] FIG. 3 illustrates a view of one example, which is viewed
from the upper side, and FIG. 4 illustrates a view which is viewed
from the side face. As is illustrated above, it is preferable to
arrange the main flow channel 12 in a horizontal direction in the
thermostatic liquid tank 28, and arrange the branch introduction
flow channels 16a to 16e in a perpendicular (vertical) direction.
This is because the arrangement space is made as small as
possible.
[0058] Subsequently, the operation of the above described reaction
apparatus 10 will now be described below. A raw material M.sub.1 is
supplied to a main flow channel 12 by a pump 20. The temperature of
the raw material M.sub.1 to be supplied to the main flow channel 12
is controlled by an adjusting flow channel 18. On the other hand, a
raw material M.sub.2 is supplied to an introduction flow channel 14
by a pump 26. The temperature of the raw material M.sub.2 to be
supplied to the introduction flow channel 14 is controlled by an
adjusting flow channel 24.
[0059] One part of the raw material M.sub.2 is branched from the
introduction flow channel 14 at a branch point of each of branch
introduction flow channels 16a to 16e in the introduction flow
channel 14, and flows to each of the branch introduction flow
channels 16a to 16e. The raw material M.sub.2 flowing through each
of the branch introduction flow channels 16a to 16e is introduced
to the main flow channel 12 at each of introduction points 12o to
12s. The raw material M.sub.2 which has been introduced to the main
flow channel 12 reacts with the raw material M.sub.1 which has been
flowing through the main flow channel 12. This reaction raises the
temperature of the fluid. The raised temperature is cooled by the
refrigerant in the thermostatic liquid tank 28. A produced liquid P
which has been produced through the reaction is collected in a
container 22.
[0060] In this reaction apparatus 10, the raw material M.sub.2 is
introduced into the main flow channel 12 at five introduction
points 12o to 12s of the main flow channel 12, so that reaction
apparatus 10 can react the raw material M.sub.1 with the raw
material M.sub.2 in a distributed way. Thereby, the reaction
apparatus can inhibit the temperature rise of the fluid due to the
introduction of the raw material M.sub.2 at one of introduction
points 12o to 12s. In this reaction apparatus 10, a temperature
rise at an introduction point is lower as the introduction points
12o to 12s is located downstream in a flow direction of the main
flow channel 12, but the reaction apparatus 10 has a structure of
making the flow channel length of the flow channel 12a between the
introduction points 12o and 12p in the main flow channel 12, in
which the temperature rise is the highest, longer than the flow
channel lengths between other introduction points 12b to 12e, and
accordingly can appropriately remove the heat. From these
descriptions, the reaction apparatus 10 according to the present
exemplary embodiment can provide high heat removal efficiency, and
accordingly can provide a high yield of a target substance.
[0061] The reaction apparatus 10 according to the present exemplary
embodiment has a larger cross-section area of a flow channel than a
microreactor, and accordingly can prevent the plug-up of the flow
channel and can secure the high productivity.
[0062] The reaction apparatus in the present embodiment can
particularly show an effect, when a nucleophilic organometallic
compound such as a Grignard reagent is used as any one of a raw
material M.sub.1 and a raw material M.sub.2. In a microreactor, the
temperature of the Grignard reagent approaches that of a
refrigerant in a flow channel because the fluid is effectively
cooled, and a speed of the fluid in the flow channel is low, so
that the plug-up of the flow channel tends to occur due to
precipitates, and a refrigerant cannot employ a temperature not
higher than a precipitation temperature as its temperature.
However, in the present embodiment, the refrigerant can employ a
temperature not higher than the precipitation temperature as its
temperature. Accordingly, the reaction apparatus can keep cooling
efficiency high, simultaneously can cool a reactive fluid in a main
flow channel 12 to a low temperature to which the microreactor
cannot cool the reactive fluid, and accordingly contribute to the
improvement of the yield of a target substance.
[0063] In addition, the reaction apparatus can very effectively
remove the heat, accordingly does not need to dilute the raw
materials M.sub.1 and M.sub.2 with an organic solvent, and can save
the organic solvent.
[0064] Specific examples of a Grignard reagent include methyl
magnesium bromide, ethyl magnesium bromide, propyl magnesium
bromide, allyl magnesium bromide, phenyl magnesium bromide, methyl
magnesium chloride, ethyl magnesium chloride, propyl magnesium
chloride, allyl magnesium chloride and phenyl magnesium
chloride.
[0065] A specific example in the case of employing the Grignard
reagent includes the following reaction. In this example, a
Grignard reagent represented by the following formula (2) adds to a
carbonyl compound represented by the following formula (1), and
then, an adduct represented by the following formula (3) is
obtained through two steps. In the formula, Ar.sup.1 represents an
aryl group.
##STR00001##
[0066] Another specific example of using the Grignard reagent
includes a reaction through which an adduct represented by the
following formula (8) is obtained when allyl magnesium chloride
represented by the following formula (7) adds to an arylaldehyde.
In the formula, Ar.sup.2 represents an aryl group, and Ar.sup.3
represents an arylene group.
##STR00002##
[0067] A reaction other than the Grignard reagent can include an
addition reaction of the nucleophilic organometallic compound with
an organocyano compound or a carbonyl compound by using an
organolithium compound such as a lithium alkyl compound, an
organozinc compound such as a zinc alkyl, an organocadmium compound
such as a cadmium dialkyl or an organosodium compound such as a
sodium alkyl, as one of the raw materials M.sub.1 and M.sub.2, and
using an organocyano compound or a carbonyl compound as the other
of the raw materials M.sub.1 and M.sub.2.
[0068] The above described organolithium compound includes lithium
methyl, lithium butyl and lithium phenyl. A carbonyl compound
includes a compound having a functional group such as an
alkylcarbonyl group, an arylcarbonyl group, an alkoxycarbonyl
group, an aryloxycarbonyl group and an amino-carbonyl group, and
specifically, an acyl group, a methoxycarbonyl group, an
ethoxycarbonyl group, a propyloxycarbonyl group, an amino-carbonyl
group and a dimethylamino-carbonyl group.
[0069] A specific example in the case of using an organolithium
compound includes the following reaction. In this example, the
reaction is caused by passing n-butyl lithium and diethylamine
through the first reaction apparatus (its introduction flow
channel) according to the present invention as a second fluid, and
passing ethylacetoacetate represented by the following formula (4)
as a first fluid (through main flow channel); and by passing the
above product through the second reaction apparatus (its
introduction flow channel) according to the present invention as a
second fluid, and passing 1-aryl-3-hexanon (through main flow
channel) as a first fluid. Thereby, the reaction apparatus
according to the present invention can be applied to a method of
obtaining 5,5-dihydro-4-hydroxy-6-(arylethyl)-6-propyl-2,
H-pyran-2-on represented by the following formula (6). In the
formula, Are represents an aryl group.
##STR00003##
[0070] This method can obtain a high total yield, by obtaining a
lithium compound which is a product to be obtained in the first
reaction apparatus according to the present invention at the
maximum yield, and continuously passing a carbonyl compound to an
apparatus to react the compounds with each other, as was described
above.
[0071] When the lithium compound (5) is held for a period of time,
it continuously disappears due to a side reaction, so that it shows
a large effect in enhancing the total yield to connect the reaction
apparatuses according to the present invention and passing the
following reactant without holding the product in the first
reaction apparatus for a period of time, as was described
above.
[0072] An exchange reaction of an active hydrogen with a metal such
as lithium or sodium can be carried out by employing an
organolithium compound such as a lithium alkyl compound or an
organosodium compound such as a sodium alkyl, as one of the raw
materials M.sub.1 and M.sub.2, and employing a compound having an
active hydrogen such as a secondary amine as the other of the raw
materials M.sub.1 and M.sub.2. For instance, lithium
diisopropylamide is obtained by employing butyl lithium and
diisopropylamine as the raw materials M.sub.1 and M.sub.2.
[0073] Furthermore, an exchange reaction of a halogen atom with a
metal such as lithium or sodium can be carried out by employing an
organolithium compound such as a lithium alkyl compound or an
organosodium compound such as a sodium alkyl, as one of the raw
materials M.sub.1 and M.sub.2, and employing an organic compound
having a halogen atom as the other of the raw materials M.sub.1 and
M.sub.2.
[0074] Still furthermore, a reduction reaction of a carbonyl
compound can be carried out by employing a metal hydride such as
lithium aluminum hydride, lithium borohydride and sodium
borohydride, a metal or an alloy as one of the raw materials
M.sub.1 and M.sub.2, and employing a carbonyl compound as the other
of the raw materials M.sub.1 and M.sub.2.
[0075] In addition to the above description, a hydrogenation of an
unsaturated compound can be carried out by employing a metal
complex having a ferroceno phosphine as a ligand as one of the raw
materials M.sub.1 and M.sub.2, and employing an unsaturated
compound as the other of the raw materials M.sub.1 and M.sub.2.
[0076] The ferroceno phosphine ligand which can be applied to this
case includes:
[0077] Josiphos ligand represented by the following chemical
formula (wherein R and R' represent an organic group);
##STR00004##
[0078] Walphos ligand represented by the following chemical formula
(wherein R and R' represent an organic group); and
##STR00005##
[0079] Mandyphos ligand represented by the following chemical
formula (wherein R and R' represent an organic group).
##STR00006##
[0080] The metallic complex having the ferroceno phosphine as a
ligand is particularly preferably a rhodium complex having the
ligand as described above.
[0081] A specific example of a hydrogenation reaction with the use
of a rhodium complex includes a chiral hydrogenation reaction
(catalytic reaction with the use of chiral uniform rhodium complex)
expressed by the following reaction formula. In the following
formula, Rh-COD represents rhodium-cyclooctadienyl; R represents a
C.sub.1 to C.sub.6 alkyl group which may be substituted with a
halogen atom; Ar represents an aryl group (which may be substituted
with a C.sub.1 to C.sub.6 alkyl group optionally substituted with a
halogen atom, or a halogen atom); and Josiphos represents the above
described Josiphos ligand (R represents a 4-trifluoromethylphenyl
group and R' represents a t-butyl group, or R represents a phenyl
group and R' represents a t-butyl group).
##STR00007##
[0082] A reaction apparatus 10 according to the present embodiment
shown in the above described FIG. 1 makes all flowing-type fine
reaction flow channels 32 arranged in the thermostatic liquid tank
28, but may not make all of them arranged in the thermostatic
liquid tank 28. For instance, similarly to the reaction apparatus
50 shown in FIG. 2, the reaction apparatus may have a structure in
which only the main flow channel 12, a part close to the main flow
channel 12 out of the branch introduction flow channels 16a to 16e,
and the adjusting flow channel 18 are arranged in the thermostatic
liquid tank 28. This structure can be applied to the cases in which
the temperature of the raw material M.sub.2 is sufficiently
controlled by controlling the temperature in the part only close to
the main flow channel 12 out of the branch introduction flow
channels 16a to 16e.
[0083] Specifically, a portion from the main flow channel 12 to 5
cm, for instance, out of the branch introduction flow channels 16a
to 16e is arranged in the thermostatic liquid tank 28.
Example 1
[0084] The present invention will now be described more
specifically below with reference to examples, but the present
invention is not limited to the following examples.
Example 1
[0085] Example 1 was carried out in a reaction apparatus 10 shown
in FIG. 1. A main flow channel 12 is a circular pipe made from
stainless steel, and introduction points 12o and 12p are 180-degree
T-shaped mixture flow channels made from stainless steel. A
Grignard reagent: 1-bromomagnesium-5-chloropentane (0.45 mol/L) was
diluted by a tetrahydrofuran solvent and the diluted solution was
used as a raw material M.sub.2. The reagent
1-bromomagnesium-5-chloropentane was prepared by adding a magnesium
powder to 1-bromo-5-chloropentane. Diethyl oxalate (7.4 mol/L)
which had not been diluted by the solvent was used as a raw
material M.sub.1. The raw material M.sub.2 and the raw material
M.sub.1 were supplied to a flowing-type fine reaction flow channel
32, at 110 mL/min and 5.1 mL/min, respectively. Used pumps 20 and
26 were a smooth flow pump made by TACMINA CORPORATION. From the
above described conditions, a mixed solution of these materials
stays in the flowing-type fine reaction flow channel 32 for
approximately 14 seconds.
[0086] The Grignard reagent and diethyl oxalate were accommodated
in a supply container and controlled at 10.degree. C. and room
temperature respectively, and a thermostatic liquid tank 28
accommodated methanol as a refrigerant 30 and was controlled at
-15.degree. C. The produced liquid was collected and quenched with
a dilute hydrochloric acid. The target substance of
ethyl-7-chloro-2-oxalic pentane was obtained in the yield of
90%.
Example 2
[0087] Example 2 was carried out in a reaction apparatus 50 shown
in FIG. 2. Here, each length of branch introduction flow channels
16a to 16e was set at 0.5 m, and a portion from a main flow channel
12 to 5 cm of branch introduction flow channels 16a to 16e was
arranged in a thermostatic liquid tank 28. The length of an
adjusting flow channel 18 was set at 1 m. Each of the flow channel
lengths of a flow channel 12a between introduction points 12o and
12p in the main flow channel 12 and a flow channel 12b between
introduction points 12p and 12q was set at 3 m, and each of the
flow channel lengths of a flow channel 12c between introduction
points 12q and 12r, a flow channel 12d between introduction points
12r and 12s and a flow channel 12e from an introduction point 12s
to an edge of the thermostatic liquid tank 28 was set at 1 m. The
other conditions were set at the same condition as in Example
1.
[0088] A Grignard reagent: 1-bromomagnesium-5-chloropentane (0.45
mol/L) was diluted by a tetrahydrofuran solvent and the diluted
solution was used as a raw material M.sub.2. Diethyl oxalate (7.4
mol/L) which had not been diluted by the solvent was used as a raw
material M.sub.1. The raw material M.sub.2 and the raw material
M.sub.1 were supplied to a flowing-type fine reaction flow channel
32, at 110 mL/min and 5.1 mL/min, respectively. From the above
described conditions, a mixed solution of these materials stays in
the flowing-type fine reaction flow channel 32 for approximately 42
seconds.
[0089] The Grignard reagent and diethyl oxalate were accommodated
in a supply container and controlled at 10.degree. C. and room
temperature respectively, and the thermostatic liquid tank 28
accommodated methanol as a refrigerant 30 and was controlled at
-15.degree. C. The produced liquid was collected and quenched with
a dilute hydrochloric acid. The target substance of
ethyl-7-chloro-2-oxalic pentane was obtained in the yield of
90%.
Example 2'
[0090] Example 2' was carried out while controlling the temperature
of a thermostatic liquid tank 28 to -5.degree. C., and setting
other conditions at the same conditions as in Example 2. As a
result, the yield of ethyl-7-chloro-2oxalic pentane was 86%.
Example 3
[0091] Example 3 was carried out in a reaction apparatus 50 shown
in FIG. 2. Here, a circular pipe having an inner diameter 3 mm and
an outer diameter 4 mm was used for the pipe which constitutes a
main flow channel 12, an introduction flow channel 14 and each of
branch introduction flow channels 16a to 16e. The lengths of the
respective branch introduction flow channels 16a to 16e were set at
0.5 m. The length of an adjusting flow channel 18 was set at 1 m.
The flow channel lengths of a flow channel 12a between introduction
points 12o and 12p in the main flow channel 12 and a flow channel
12b between introduction points 12p and 12q were each set at 3 m,
and the flow channel lengths of a flow channel 12c between
introduction points 12q and 12r, a flow channel 12d between
introduction points 12r and 12s and a flow channel 12e from an
introduction point 12s to an edge of a thermostatic liquid tank 28
were set at 1 m respectively. The other conditions were the same as
in Example 1.
[0092] A Grignard reagent: 1-bromomagnesium-5-chloropentane (0.45
mol/L) was diluted by a tetrahydrofuran solvent and the diluted
solution was used as a raw material M.sub.2. Diethyl oxalate (7.4
mol/L) which had not been diluted by the solvent was used as a raw
material M.sub.1. The raw material M.sub.2 and the raw material
M.sub.1 were supplied to a flowing-type fine reaction flow channel
32, at 965 mL/min and 47 mL/min, respectively. From the above
described conditions, a mixed solution of these materials stays in
a flowing-type fine reaction flow channel 32 for approximately 4.9
seconds.
[0093] The Grignard reagent and diethyl oxalate were accommodated
in a supply container and controlled at 10.degree. C. and room
temperature respectively, and the thermostatic liquid tank 28
accommodated methanol as a refrigerant 30 and was controlled at
-30.degree. C. The produced liquid was collected and quenched with
a dilute hydrochloric acid. The target substance of
ethyl-7-chloro-2-oxalic pentane was obtained in the yield of
88%.
Example 4
[0094] Example 4 was carried out in a reaction apparatus 50 shown
in FIG. 2. Here, a circular pipe having an inner diameter 1 mm and
an outer diameter 3 mm was used for the pipe which constitutes a
main flow channel 12. A circular pipe having an inner diameter 3 mm
and an outer diameter 4 mm was used for the pipe which constitutes
an introduction flow channel 14. A circular pipe having an inner
diameter 1 mm and an outer diameter 3 mm was used for the pipe
which constitutes each of branch introduction flow channels 16a to
16e. Lengths of branch introduction flow channels 16a to 16e were
set at 0.5 m, 1.5 m, 2.0 m, 2.5 m and 3.0 m respectively, and
portions from the main flow channel 12 to 5 cm of all branch
introduction flow channels were arranged in a thermostatic liquid
tank 28. The length of an adjusting flow channel 18 was set at 1 m.
The flow channel length of a flow channel 12a between introduction
points 12o and 12p in the main flow channel 12 was set at 1.0 m,
and the flow channel lengths of a flow channel 12b between
introduction points 12p and 12q, a flow channel 12c between
introduction points 12q and 12r, a flow channel 12d between
introduction points 12r and 12s, and a flow channel 12e from an
introduction point 12s to an edge of the thermostatic liquid tank
28 were set at 0.5 m respectively. The other conditions were the
same as in the above described reaction apparatus 10.
[0095] A Grignard reagent: 1-bromomagnesium-5-chloropentane (0.45
mol/L) was diluted by a tetrahydrofuran solvent and the diluted
solution was used as a raw material M.sub.2. Diethyl oxalate (7.4
mol/L) which had not been diluted by the solvent was used as a raw
material M.sub.1. The raw material M.sub.2 and the raw material
M.sub.1 were supplied to a flowing-type fine reaction flow channel
32, at 109 mL/min and 5.1 mL/min, respectively. From the above
described conditions, a mixed solution of these materials stays in
the flowing-type fine reaction flow channel 32 for approximately
1.6 seconds.
[0096] The Grignard reagent and diethyl oxalate were accommodated
in a supply container and controlled at 10.degree. C. and room
temperature respectively, and the thermostatic liquid tank 28
accommodated methanol as a refrigerant 30 and was controlled at
-15.degree. C. The produced liquid was collected and quenched with
a dilute hydrochloric acid. The target substance of
ethyl-7-chloro-2-oxalic pentane was obtained in the yield of
90%.
Example 4'
[0097] Example 4' was carried out while controlling the temperature
of a thermostatic liquid tank 28 to 5.degree. C., and setting other
conditions at the same conditions as in Example 4. As a result, the
yield of ethyl-7-chloro-2oxalic pentane was 89%.
Example 5
[0098] Example 5 was carried out in a reaction apparatus 50 shown
in FIG. 2. Here, a circular pipe having an inner diameter 1 mm and
an outer diameter 3 mm was used for the pipe which constitutes a
main flow channel 12. A circular pipe having an inner diameter 3 mm
and an outer diameter 4 mm was used for the pipe which constitutes
an introduction flow channel 14. A circular pipe having an inner
diameter 1 mm and an outer diameter 3 mm was used for the pipe
which constitutes each of branch introduction flow channels 16a to
16e. Each length of branch introduction flow channels 16a to 16e
was set at 0.5 m, and portions from the main flow channel 12 to 5
cm of all the branch introduction flow channels 16a to 16e were
arranged in a thermostatic liquid tank 28. The length of an
adjusting flow channel 18 was set at 1 m. The flow channel length
of a flow channel 12a between introduction points 12o and 12p in
the main flow channel 12 was set at 1.0 m, and the flow channel
lengths of a flow channel 12b, a flow channel 12c, a flow channel
12d, and a flow channel 12e respectively between introduction
points 12p and 12q, between introduction points 12q and 12r,
between introduction points 12r and 12s, and from an introduction
point 12s to an edge of the thermostatic liquid tank 28 were set at
0.5 m. The other conditions were the same as in the above described
reaction apparatus 10.
[0099] A Grignard reagent: 1-bromomagnesium-5-chloropentane (0.45
mol/L) was diluted by a tetrahydrofuran solvent and the diluted
solution was used as a raw material M.sub.2. Diethyl oxalate (2.0
mol/L) which had been diluted by the same solvent was used as a raw
material M.sub.1. The raw material M.sub.2 and the raw material
M.sub.1 were supplied to a flowing-type fine reaction flow channel
32, at 100 mL/min and 17 mL/min, respectively. From the above
described conditions, a mixed solution of these materials stays in
the flowing-type fine reaction flow channel 32 for approximately
1.4 seconds.
[0100] The Grignard reagent and diethyl oxalate were accommodated
in a supply container and controlled at 10.degree. C. and room
temperature respectively, and the thermostatic liquid tank 28
accommodated methanol as a refrigerant 30 and was controlled at
-15.degree. C. The produced liquid was collected and quenched with
a dilute hydrochloric acid. The target substance of
ethyl-7-chloro-2-oxalic pentane was obtained in the yield of
84%.
Comparative Example 1
[0101] The above described reaction was carried out by using a
microreactor system made by Cellular Process Chemistry GmbH. The
Grignard reagent: 1-bromomagnesium-5-chloropentane (0.45 mol/L) was
diluted by a tetrahydrofuran solvent and the diluted solution was
used as a raw material M.sub.2. Diethyl oxalate (5.5 mol/L) which
had been diluted by the same solvent was used as a raw material
M.sub.1. The raw material M.sub.2 and the raw material M.sub.1 were
supplied to a flowing-type fine reaction flow channel, at 16 mL/min
and 1 mL/min, respectively. The reaction apparatus was kept at
-5.degree. C. by an attached temperature controller. The yield of a
target substance was 84%, but plug-up occurred and the raw
materials could not be supplied on the way.
Comparative Example 2
[0102] In comparison with Example 3, branch introduction flow
channels 16a to 16e to be connected to the main flow channel 12
were made to be one channel instead of 5 channels. Comparative
example 2 was carried out under the same conditions as in Example
3, except the above described condition. The yield of a target
substance was 74%.
[0103] (Result)
[0104] The result of the above described examples will now be
described together in the following Table.
TABLE-US-00001 TABLE 1 Example Example Example 1 Example 2 2'
Example 3 Example 4 4' Example 5 reaction reaction reaction
reaction reaction reaction reaction reaction apparatus apparatus
apparatus apparatus apparatus apparatus apparatus apparatus 10 50
50 50 50 50 50 pipe of outer outer outer outer outer outer outer
main flow diameter diameter diameter diameter diameter diameter
diameter channel 12 4 mm 4 mm 4 mm 4 mm 3 mm 3 mm 3 mm inner inner
inner inner inner inner inner diameter diameter diameter diameter
diameter diameter diameter 3 mm 3 mm 3 mm 3 mm 1 mm 1 mm 1 mm 12a
1.0 m 3.0 m 3.0 m 3.0 m 1.0 m 1.0 m 1.0 m 12b 0.5 m 3.0 m 3.0 m 3.0
m 0.5 m 0.5 m 0.5 m 12c 0.5 m 1.0 m 1.0 m 1.0 m 0.5 m 0.5 m 0.5 m
12d 0.5 m 1.0 m 1.0 m 1.0 m 0.5 m 0.5 m 0.5 m 12e 0.5 m 1.0 m 1.0 m
1.0 m 0.5 m 0.5 m 0.5 m pipe of outer outer outer outer outer outer
outer introduction diameter diameter diameter diameter diameter
diameter diameter flow 4 mm 4 mm 4 mm 4 mm 4 mm 4 mm 4 mm channel
14 inner inner inner inner inner inner inner diameter diameter
diameter diameter diameter diameter diameter 3 mm 3 mm 3 mm 3 mm 3
mm 3 mm 3 mm 14a 1.0 m 0.5 m 0.5 m 1.0 m 0.5 m 0.5 m 0.5 m 14b 0.5
m 0.5 m 0.5 m 1.0 m 0.5 m 0.5 m 0.5 m 14c 0.5 m 0.5 m 0.5 m 1.0 m
0.5 m 0.5 m 0.5 m 14d 0.5 m 0.5 m 0.5 m 1.0 m 0.5 m 0.5 m 0.5 m
pipe of outer outer outer outer outer outer outer branch diameter
diameter diameter diameter diameter diameter diameter introduction
3 mm 3 mm 3 mm 4 mm 3 mm 3 mm 3 mm flow inner inner inner inner
inner inner inner channel 16 diameter diameter diameter diameter
diameter diameter diameter 1 mm 1 mm 1 mm 3 mm 1 mm 1 mm 1 mm 16a
0.5 m 0.5 m 0.5 m 0.5 m 0.5 m 0.5 m 0.5 m 16b 0.5 m 0.5 m 0.5 m 0.5
m 1.5 m 1.5 m 0.5 m 16c 0.5 m 0.5 m 0.5 m 0.5 m 2.0 m 2.0 m 0.5 m
16d 0.5 m 0.5 m 0.5 m 0.5 m 2.5 m 2.5 m 0.5 m 16e 0.5 m 0.5 m 0.5 m
0.5 m 3.0 m 3.0 m 0.5 m arrangement 0.5 m 5 cm 5 cm 5 cm 5 cm 5 cm
5 cm length of thermostatic liquid tank 28 of branch introduction
flow channel 16 thermostatic -15.degree. C. -15.degree. C.
-5.degree. C. -30.degree. C. -15.degree. C. 5.degree. C.
-15.degree. C. liquid tank 28 yield 90% 90% 86% 88% 90% 89% 84%
[0105] The reactions according to the above described examples are
an exothermic reaction (reaction heat: approximately 100 kJ/mol),
so that it becomes necessary for inhibiting the production of a
reaction product and effectively producing a target substance to
remove a heat which has been generated through the reaction with
high efficiency, and to keep the temperature in a main flow channel
12 which is a reaction flow channel at as low a temperature as
possible. The equivalent diameter of the main flow channel 12 in
the examples is 1 to 3 mm, which can inhibit the temperature from
rising. Furthermore, the reaction apparatus of the present
invention adopts a structure which is formed of a main flow
channel, an introduction flow channel and a branch introduction
flow channel having simple and easy flow channel diameters and
lengths, and a system which has a plurality of branch introduction
flow channels, and thereby can distribute the reaction heat to be
generated at an introduction point and can remove the heat from the
reaction fluid more effectively so as to set the temperature in a
flow channel at a predetermined temperature.
[0106] In addition, reaction apparatuses 10 and 50 according to the
present examples could provide a higher reaction yield than a
microreactor system. Furthermore, the flow channel of the
microreactor system was very small, and frequently caused plug-up
therein. However, the reaction apparatuses 10 and 50 according to
the present examples had flow channels with diameters of 1 to 3 mm,
and accordingly did not cause the plug-up at all. The microreactor
system is largely affected by a pressure loss in the flow channel,
and accordingly could not send a large amount of flow rates.
However, the reaction apparatuses 10 and 50 according to the
present examples are less affected by the pressure loss, can send a
large amount of flow rates, accordingly can be stably operated
continuously for a long period of time, and is suitable for a
high-volume production.
* * * * *